Depending on the presence of a Y-chromosome, the bipotential mammalian gonad becomes a testis or an ovary and gender-specific genes ensure appropriate gonadogenesis and sex development. Using two-dimensional gel electrophoresis and mass spectrometry, protein expression profiles of newborn normal and FIGLA null newborn ovaries were compared. The detection of testis-specific proteins in FIGLA null newborn ovaries suggested repression of male sex-specific genetic pathways. To further investigate this hypothesis, transgenic mouse lines ectopically expressing FIGLA in male germ cells under a human spermatogonial-specific (hTSPY) promoter were established. Although initially fertile, transgenic male mice had decreased fecundity and testicular size 73% of normal. The expression of seven male germ cell-specific genes observed in normal mice was transcriptionally down-regulated in mature transgenic testes. Although all stages of spermatogenesis were initially detected, vacuoles were sporadically observed within seminiferous tubules consistent with patches of germ cell apoptosis. As transgenic male mice aged, there was further progressive depletion of germ cell lineages coupled with a increased vacuolization and apoptosis. This escalating severity of gonadal histopathology correlated with decreased fertility that was complete by 5 months when dramatic reductions in sperm counts and poor motility abolished the ability of transgenic sperm to bind and fertilized normal eggs in vitro. Collectively, these data high-light FIGLA both as an activator oocyte-specific and as a repressor of testis-specific genes necessary for successful development of the female gonad.